Complement C5 Inhibition and Short-Term Cardiovascular Outcomes After Acute Limb Ischemia: A Real-World Cohort Study

Background: Acute limb ischemia (ALI) is a vascular emergency characterized by abrupt limb hypoperfusion, ischemia–reperfusion injury, and a high risk of thromboinflammatory and organ complications. Complement activation has been implicated in endothelial dysfunction, glycocalyx injury, and ischemia–reperfusion damage, but the clinical relevance of ongoing terminal complement blockade in patients presenting with ALI remains unclear, highlighting a gap between mechanistic understanding and real-world clinical outcomes. Methods: A retrospective cohort study was performed using the TriNetX federated research network. Adult patients with ALI were identified and stratified according to ongoing treatment with the C5 inhibitors eculizumab or ravulizumab. Outcomes included ischemic stroke, venous thrombosis, pulmonary embolism, arterial embolism, thrombotic disorders, acute kidney injury (AKI), and the composite outcome major adverse cardiovascular events (MACE) within 31 days. Propensity score matching was performed for demographic characteristics, cardiovascular comorbidities, complement-associated diseases and medications. Results: After propensity score matching, 112 patients remained in each cohort. Compared with matched controls, patients receiving C5 inhibition had a significantly higher risk of venous thrombosis (27.9% vs. 13.7%; p < 0.001), AKI (18.9% vs. 9.4%; p = 0.001), MACE (50.0% vs. 35.1%; p = 0.001), and thrombotic disorders (46.7% vs. 31.3%; p = 0.001). Time-to-event analyses confirmed significantly lower event-free survival for venous thrombosis (HR 2.3), AKI (HR 2.1), MACE (HR 1.6), and thrombotic disorders (HR 1.7). No significant differences were observed for ischemic stroke, pulmonary embolism, or arterial embolism. Conclusions: In patients with ALI, ongoing treatment with eculizumab or ravulizumab was not associated with an apparent reduction in short-term thromboinflammatory or cardiovascular complications. Instead, the observed outcome pattern suggests persistent vulnerability in this clinically uncommon but increasingly relevant high-risk population, although substantial residual confounding by indication and disease severity remains likely. These findings support further investigation of complement-targeted therapy, endothelial injury, and short-term vascular outcomes in ALI, and emphasize the translational relevance of linking mechanistic insights with clinical data to inform risk stratification and management strategies in this population.